N,N -Dichlorovaleramide: An Efficient Decontaminating Reagent for Sulfur Mustard

N,N-Dichlorovaleramide: An Efficient Decontaminating Reagent forSulfur MustardPranav K. Gutch*,† and Avik Mazumder‡

†Synthetic Chemistry Division, and ‡Vertox Laboratory Defence R and D Establishment, Jhansi Road, Gwalior-474002 (MP), India

*S Supporting Information

ABSTRACT: An efficient and operationally simple method for the chemical decontamination of sulfur mustard (HD) has beenreported herein. A newly synthesized (positive chlorine bearing) reagent N,N-dichlorovaleramide has been utilized for thispurpose. Decontamination has been achieved in aqueous and aprotic media. The reaction was monitored by gaschromatography−mass spectrometry and NMR spectroscopy. This reagent is more effective, stable, economical, and easy tosynthesize and leads to instant decontamination of HD. The reaction was found to instantaneously and completely convert HDto innocuous products at different temperatures (−10 to 25 °C).

1. INTRODUCTIONThe cytotoxic and persistent blistering agent sulfur mustard(HD) was used as a chemical warfare agent (CWA)1 duringWorld War I and also in the Iraq−Iran conflict2 (1980−1988).To get rid of its toxic effects, decontamination is of primeimportance. A reaction can be used for effective decontamina-tion of HD only if the reaction can instantly convert HD intonontoxic products. Diverse types of reactions (viz. nucleophilicdisplacement, elimination, and oxidation, etc.) have been triedto achieve this goal.Among the various methods reported for the decontamina-

tion3−6 of HD, hydrolysis and oxidative methods are the mostimportant. Hydrolytic decontamination7 of HD has limitedpractical utility due to limited cosolubility of HD and inorganicbases in a common solvent. Moreover, it is difficult when alarge quantity of HD is present. The toxic intermediates(formed during the reversible hydrolytic reactions) causerecurring toxicity. Moreover, solubility and rate of hydrolysisdecreases appreciably with the decrease in temperature. Thepractical utility of alternative methods such as hydrogenolysis8

is also limited.Owing to the presence of oxidizable bivalent sulfur, a variety

of oxidative routes (viz. hydrothermal oxidation,9 electro-chemical oxidation;10 oxidation using organic chloramines,11

sodium hypochlorite,12 enzyme based micro emulsions,13,14

zeolites,15 iodobenzoic acid complex,16 titania nanotubes,17

peroxides18) have been tried for decontamination of HD. Mostof these reagents require prolonged reaction time,19,20 they aredifficult to synthesize21,22 and/or make use of hazardoussolvents and aggressive reaction conditions.This prompted us to explore the possibility of developing a

stable, easy to synthesize, cost-effective, and efficient positivechlorine releasing reagent. The reagent, N,N-dichlorovaler-amide, can be quantitatively produced in high purity within aminimal reaction time. The ease of synthesis and simpleworkup renders the method convenient for upscaling. Wereport herein the synthesis of this reagent and its use forinstantaneous decontamination of HD. Since HD has limitedsolubility in aqueous systems, the decontamination reactions

were first tried in aprotic medium. After its success, it wasextended to decontamination of HD in aqueous systems. Totest applicability of this reagent for decontamination of HD atdifferent temperatures, the reactions were carried out attemperatures ranging from −10 to 25 °C.

2. EXPERIMENTAL SECTION2.1. Materials and Methods. Valeramide, 3-trimethylsilyl

propionic acid-d4 (TSP), chloroform-d1, and acetonitrile-d3

were purchased from Sigma Aldrich Chemical Co., Milwaukee,USA. Acetonitrile and glacial acetic acid of AR grade werepurchased from SD. Fine-Chem Ltd., India. Sodiumhypochlorite was prepared by passing chlorine gas at a flowof 1 g/min in NaOH solution (15%, 100 mL) for 30 min at 5°C. HD was prepared23 in house with purity >99%. Purity waschecked by GC and GC−MS

2.2. Instruments Used and Conditions of Analysis.Infrared (IR) spectra were recorded (in neat condition) on aPerkin-Elmer, USA, make BX-2 FT-IR spectrophotometer(resolution, 4 cm−1). Identification of the products of thedecontamination reaction was performed by GC−MS instru-ment (in EI mode) consisting of a 7890 Agilent GC coupledwith 5975C mass selective detector (Agilent Technologies, SanJose, CA, USA) in order. GC−MS experiments were carriedout on BP-5 column (30 m × 0.250 mm 0.25 μm film thickness

Received: August 15, 2011Revised: April 2, 2012Accepted: April 7, 2012Published: April 8, 2012

Scheme 1. Synthesis of N,N-Dichloroacetamide/valeramide(1)

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of the stationary phase) with the following temperatureprogram: 80 °C for 2 min, followed by a linear gradient to250 at 10 °C per minute and held at 250 °C for 5 min.The EI analysis was performed at 70 eV with ion source

temperature at 200 °C and emission current of 400 μA. TheGC-FPD (S-mode) analyses were carried out on a Chemitomake instrument. The GC conditions used were as follows;column HP-5 (30 m × 0.250 mm, 0.25 μm film thickness of thestationary phase) with a temperature program of 50 °C for 2min followed by a linear gradient to 250 at 10 °C min−1, andheld at 250 °C for 5 min. The injector temperature wasmaintained at 250 °C while the transfer line was at 280 °C.All NMR spectra were recorded on 400 MHz Bruker AV II

spectrometer equipped with a broadband inverse probe head.The variable temperature unit of the spectrometer was used forcarrying out the reactions at −10, −5, 0, 10, 15, and 25 °C in 5mm NMR tubes. All the reactants and solvents wereequilibrated for 10 min at the temperature at which theexperiments were performed. Eight scans and four dummyscans were used for recording the solvent suppressed spectra

using Bruker presaturation pulse program zgpr. The data wereFourier transformed and processed with a Gaussian baselinecorrection function with a filter width of 1 ppm to suppress theresidual solvent peak.

2.3. Synthesis of N,N-dichlorovaleramide/N,N-Dichlor-oacetamide. A mixture of valeramide or acetamide (0.1 mol)and glacial acetic acid (30 mL) were taken in a two neckedround-bottom flask (scheme 1) mounted on a magnetic stirrer.It was equipped with condenser and dropping funnel. Thereaction mixture was cooled to 5 °C in an ice-bath and sodiumhypochlorite (12−15%, 25−30 mL) was added slowly with thehelp of a dropping funnel over a period of 15 min with stirring.Acetic acid (5−10 mL) was added slowly maintaining pH of thereaction mixture at 6−6.5. The reaction was allowed to proceedfor 15 min. Thereafter, the translucent yellow organic layercontaining the product was isolated from the supernatantaqueous layer. It was washed with water and dried overanhydrous sodium sulfate. The yellow oily liquid was distilledunder vacuum to obtain N,N-dichlorovaleramide (b.p. 44−45°C at 6.0 mm Hg, isolated yield ∼95%) or N,N-

Figure 1. GC−FPD (S mode) of HD (a) before reaction (b) after the reaction in aprotic medium.

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dichloroacetamide. The positive chlorine content of thereagents was estimated by standard iodometric titration,24

and its structure was confirmed by IR and NMR spectroscopy.2.4. Stability Study of the Reagent. N,N-dichlorovaler-

amide (or N,N-acetamide) was prepared by the methodreported herein. It was stored in a stoppered glass vial atroom temperature. Active chlorine was determined periodically

by iodometric titration over a period of 2 years. It was observedthat the compound was highly stable during this period andactive chlorine content was found to decrease marginally [from100 (44%) to 92% (43.12%)] during this period.

2.5. Process for the Neutralization of HD in AproticMedium. N,N-dichlorovaleramide (3.0 mmol) was added to astirred solution of HD (1.0 equiv) in acetonitrile (5 mL). The

Figure 2. (a) NMR spectra of HD (5 μL) (b) N,N dichlorovaleramide (7.5 μL) (c) reaction mixture containing NMR spectra of HD (5 μL) andN,N dichlorovaleramide (7.5 μL). All NMR spectra were recorded at −10 °C in 400 μL CH3CN:H2O mixture (9:1), locked and referenced withrespect to TSP dissolved in CD3CN:H2O (9:1) taken in a stem coaxial insert.



reaction was carried out at room temperature (35 °C), and thereaction was monitored by GC-FPD operating in sulfur mode(Figure 1). It was found that HD was decontaminatedinstantaneously in aprotic medium. Since the ultimate objectiveof the present study was to achieve instantaneous decontami-nation in aqueous medium, the reaction mixtures weremonitored by GC−MS and NMR spectroscopy to check fordisappearance of HD.2.6. Process for the Neutralization of HD in Aqueous

Medium. N,N-dichlorovaleramide (1) (0.01 mol) was addedto a stirred solution of HD (2) (0.01 mol) in 3 mL ofCH3CN:H2O mixture (9:1). Aliquots were taken at differenttime intervals (up to 5 min) and extracted with dichloro-methane (5 mL). The organic phase was analyzed for theresidual HD and degradation products by GC−MS.The reaction was also studied by variable temperature 1H

NMR spectroscopy (Figure 2). To 5 μL of HD dissolved in 400μL of CH3CN:H2O mixture (9:1), 7.5 μL of N,N-dichlorovaleramide was added, and the contents were mixedon a vortex shaker momentarily before recording the spectra onthe preconditioned NMR instrument. The samples were fieldfrequency locked and referenced with respect to TSP dissolvedin a CD3CN:H2O mixture (9:1) taken in a stem coaxial insert.The reactions and the subsequent NMR experiments werecarried out at the temperatures of −10, −5, 0, 10, 15, and 25°C. The reaction was found to proceed instantaneously even at

−10 °C. Efforts were also made to identify the reactionproducts by 1H (Figure 2), 13C{1H}, COSY, TOCSY, 1H−13CHSQC, and 1H−13C HMBC experiments (refer to SupportingInformation).

3. RESULTS AND DISCUSSION

Decontamination of HD was studied with N,N-dichlorovaler-amide at different temperatures. The NMR studies indicatedinstantaneous decontamination of HD in the reaction mixture,at −10 °C and at 25 °C. The 1H NMR spectrum showedseveral overlapped resonances in the region of 3.8−4.9 ppm,which were absent in either of the reactants. These signals wereattributed to the degradation products of HD formed after thereaction with N,N-dichlorovaleramide.To confirm the absence of HD in the products, the starting

materials and the reaction mixtures were analyzed by NMR 1H,13C{1H}, 1H−1H COSY, 1H−13C HSQC 1H−13C HMBC andGC−MS techniques (refer to Figures 1 and 2 and SupportingInformation). The experiments were carried out immediatelyafter the reactants were mixed. The results clearly showed theinstantaneous disappearance of HD and the absence of thecharacteristic 3JH−H of its vicinal protons. No discerniblechanges were observed in the spectra of the reaction mixturesthat was recorded after they were stored for 24 h at roomtemperature. These results indicated instantaneous reaction and

Figure 3. (a) Total ion chromatogram of HD before decontamination (b) mass spectrum of HD (2).



Figure 4. continued



the formation of stable products. Moreover the extracted ionchromatogram of GC−MS and NMR experiments carried outstandard addition of the toxic product showed the absence of,1-(2-chloroethylsulfonyl)-2-chloroethane, the product formedby double oxidation of HD.Although, reports are available on the identification of

reaction products of HD by NMR spectroscopy,25−27 it was topossible to identify the reaction products conclusively due tosignal overlap in the 1H NMR dimension of 1H−1H COSY,1H−13C HSQC, and 1H−13C HMBC experiments.

Therefore to confirm identities of the reaction productsconclusively, GC−EI−MS experiments were also performed.The resulting signals of the total ion chromatogram weresubjected to database search. These experiments clearly showedthat two major products; bis(2-chloroethyl)sulfoxide (3), 2-chloro 1,2-dichloroethyl sulfoxide(4), and a small quantity of 2-chloroethyl disulfide (5) are formed (Figures 3 and 4 and Table1). The match factors of the database search showed a matchfactor greater than 95%. On the basis of these structures andproduct composition, the mechanism of the decontaminationreaction was proposed (Scheme 2).In aqueous medium, (Scheme 2) HD was converted28 into a

series of oxidation and elimination products. The first step inchlorination of sulfide is the electrophilic attack of chlorine onthe sulfur atom. This generates sulfonium ion (a) thatsubsequently undergoes nucleophilic displacement of chlorineby water with concomitant elimination of HCl from structure b.The corresponding bis(2-chloroethyl)sulfoxide (3) was thusproduced. Further at higher concentrations of N,N-dichlor-ovaleramide, α-chlorination of sulfoxide (3) via intermediatestructures c and d producing 2-chloroethyl 1,2-dichloroethyl-sulfoxide (4) takes place.In addition to these, some trace amount of 2-chloroethyl

disulfide (5) is also formed via a free radical pathway. N-chloramines, in which chlorine is directly attached to nitrogen,can generate positively charged chlorine (Cl+) which is anoxidizing species. Since, HD bears oxidizable bivalent sulfuratom; and since oxidation reactions are relatively faster than

Figure 4. (a) Gas chromatogram of HD after decontamination in aqueous medium. Mass spectra of the products (b) bis-2-chloroethyl sulfoxide, (c)2-chloro-1,2-dichloroethyl sulfoxide, (d) 2-chloroethyl disulfide.

Table 1. Composition of the Product of Decontamination of HD in Aqueous Medium

1Identified by GC−MS.

Scheme 2. Mechanism of Decontamination of HD inAqueous Medium



hydrolysis reactions, corresponding sulfoxide and α-chlorinatedsulfoxides are formed in aqueous medium. This oxidationprocess yields products of lower toxicity than that of the parentcompound.29,30

Comparative studies carried out with N,N-dichloroacetamide,in order to investigate the effect of the length of alkyl chain onstability and efficiency of the reagent. As logic would suggest,this reagent was found to be more reactive than N,N-dichlorovaleramide, and it efficiently converted HD to itscorresponding sulfoxide as the major product. Because of itsinherent instability, it was difficult to prepare N,N-dichlor-oacetamide in sufficient purity and good yields, since stability isan important requirement for developing a decontaminationformulation. The reactions of N,N-dichloroacetamide werehighly exothermic. It was found to decompose readily onstorage. Therfore, the longer shelf life of N,N-dichlorovaler-amide, as compared to its lower homologue and other reportedN,N-dichlorosulfonamides (viz. chloramines-T) was an im-portant criterion for selection of this reagent for decontami-nation of HD.

4. CONCLUSIONThe study reveals that N,N-dichlorovaleramide is an easy tosynthesize, bench stable liquid reagent. It works as an excellenthomogeneous decontaminating agent against HD in aqueousmedium at room temperature. This reagent has advantage overearlier reported reagent30 in terms of stability, reactivity,effectiveness, ease of synthesis, cost of raw materials, activechlorine content. Moreover, it instantaneously decontaminatesHD at different temperatures from −10 to 25 °C.

■ ASSOCIATED CONTENT*S Supporting InformationAdditional information as described in the text. This material isavailable free of charge via the Internet at http://pubs.acs.org.

■ AUTHOR INFORMATIONCorresponding Author*E-mail: [email protected]. Tel.:+91-751-2340245. FaxNo. +91-751-2341148.NotesThe authors declare no competing financial interest.

■ ACKNOWLEDGMENTSWe thank Dr. M. P. Kaushik, Director DRDE and Dr. D. K.Dubey, Joint Director, DRDE, Gwalior, for their keen interestin the work.

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N,N -Dichlorovaleramide: An Efficient Decontaminating Reagent for Sulfur Mustard